Cancer is a multi-step process caused by genetic abnormalities in proto-oncogenes and tumor suppressor[unreadable] genes. A highly specific and effective form of cancer therapy may be to target the repair, replacement or[unreadable] inactivation of oncogenes. Indeed, we and others have shown that the inactivation of a single oncogene can[unreadable] induce sustained tumor regression. However, we have also shown that tumors can escape dependence[unreadable] upon oncogenes. Now, to better interrogate the mechanisms by which oncogenes initiate and sustain[unreadable] tumorigenesis, we have generated a transgenic model in which we can temporally regulate, alone or in[unreadable] combination the expression of oncogenes, to study in vivo the kinetics of oncogene induced tumor[unreadable] regression upon oncogene inactivation. We have begun to use this strategy to examine how oncogene[unreadable] inactivation induces tumor regression, the role of host immune mechanisms to mediate this tumor regression[unreadable] and the genetic mechanisms by which cancers escape dependence upon oncogenes. We have obtained[unreadable] several potentially important preliminary results. First, we have found that when tumors are transplanted into[unreadable] immune compromised hosts, oncogene inactivation is much less capable of inducing tumor regression.[unreadable] These results suggest that immune mechanisms play a key role in mediating tumor regression upon[unreadable] oncogene inactivation. Second, we have used Spectral Karyotypic Analysis (SKY) and CGH Microarrays to[unreadable] demonstrate that tumors that escape dependence upon oncogenes have acquired novel chromosomal[unreadable] translocations. Our expectation is that both cell extrinsic and intrinsic mechanisms are involved tumor[unreadable] escape from oncogene dependence. In some cases, these mechanisms may converge. Thus, there are[unreadable] likely to be genetic events that impair the response of tumor cells to a host mediated suppression of[unreadable] tumorigenesis.